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Promoting the M1-to-M2 Macrophage Transition to Enhance Angiogenesis

Friday, August 28, 2020

1:30 PM-3:30 PM

BIOMED PhD Research Proposal

Promoting the M1-to-M2 Macrophage Transition to Enhance Angiogenesis

Erin O'Brien, PhD Candidate
School of Biomedical Engineering, Science and Health Systems
Drexel University

Kara Spiller, PhD
Associate Professor
School of Biomedical Engineering, Science and Health Systems
Drexel University

Dysfunctional angiogenesis is implicated in several pathologies that affect tens of millions of patients in the U.S. alone. A lack of healthy vascularization can result in lethal complications, including tissue death and limb amputation, and current solutions fail to promote stable vasculature. Therefore, there is a demand for strategies that can support healthy vascularization throughout the angiogenic process. As high-level regulators of angiogenesis and healing, macrophages are an attractive target for pro-angiogenic cell therapies. Intensely responsive to environmental stimuli, macrophages have been shown to exhibit a pro-inflammatory (M1) phenotype in early healing, then a less-inflammatory M2 phenotype dominates later stages.

Although the roles of macrophage phenotypes in angiogenesis are poorly understood, studies suggest that M1 macrophages induce sprouting of new blood vessels, then M2 macrophages promote stabilization. In vivo, the M2 population can derive from circulating monocytes, or from the phenotypic switching of pre-existing M1 macrophages, but it is unknown to what extent each group is present or what they contribute to angiogenesis.

We have previously shown that M1 macrophages appear to become primed for the phenotypic switch to M2, partially via upregulation of the receptor for IL-4, one of the primary M2-promoting cytokines. This finding informed our hypothesis that M1-derived M2 macrophages are a unique phenotype essential to angiogenesis, and that promoting the M1-to-M2 switch with biomaterials will enhance angiogenesis in vivo. We will first determine the effects of M1 activation on subsequent M2 polarization by comparing the response of unactivated (M0) and M1 macrophages to IL-4. Then we will thoroughly investigate the functional differences between M0-derived and M1-derived M2 macrophages using next-generation sequencing, producing the unique gene signatures of each group.

Next, PLGA microparticles will be loaded with the M2-promoting drug simvastatin, then co-cultured with M0 or M1 macrophages to facilitate phagocytosis. The macrophages will then be injected into a murine model of hindlimb ischemia, and as the microparticles degrade and release simvastatin, the drug will promote M2 polarization intracellularly. It is expected that the group undergoing the M1-to-M2 transition will augment angiogenesis. This study will increase our understanding of the roles of macrophage phenotype during angiogenesis and will result in a translational pro-angiogenic biomaterials-based cell therapy.

Contact Information

Natalia Broz

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